This project will support a mulfidisciplinary team that combines mathematical modeling and in-vivo experiments with the following goals to: (1) investigate the interactions between tumor vascularity, blood flow, metabolic phenotype that govern physical parameters in the microenvironment, and (2) gain understanding on the role of physical parameters (particulariy the p02 and extracellular pH) in tumor growth and metastases. Experimental work will be performed in the PIs laboratory as well as the Small Animal Imaging Laboratory, SAIL, as part of Core A (Imaging). The modeling work will be performed within the Integrative Mathematical Oncology (IMO) program as well as within Core B (Math). In previous work, mathemafical models of the interactions of the tumor microenvironment and cellular phenotype and behavior have been built upon and integrated with in-vitro and in-vivo experiments. However, the current models are limited by the absence of tumor vascular dynamics that incorporate angiogenesis, vessel maturation and decay, and chaofic blood flow. To achieve this, our experimental approach will be guided by biologically realistic mathemafical models. Consistent with this research strategy, all of the mathematical models will be parameterized with experimentally determined values, and model predictions will be tested in-vivo using MRI ora dorsal skin-fold chamber. The accuracy and limitations of signal extraction from images and their relationship to the mathematical models will also be examined in collaboration with Drs. Barrett and Kupinski at the Centerfor Gamma Ray Imaging (CGRI). Some of these experiments will employ a new imaging technology that combines fluorescent microscopy with high (40 micron) resolution imaging through a novel /S*'